11-1835939-G-C

Position:

• chr11-1835939-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001394072.1(SYT8):​c.312G>C​(p.Trp104Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SYT8 NM_001394072.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

Genes affected

SYT8 (HGNC:19264): (synaptotagmin 8) This gene encodes a member of the synaptotagmin protein family. Synaptotagmins are membrane proteins that are important in neurotransmission and hormone secretion, both of which involve regulated exocytosis. Expression of the encoded protein in human pancreatic islets has been connected to activity of the promoter for the insulin gene, on the same chromosome several hundred kilobases away (PMID: 21336277 and 22928559). This association would link response to gluclose to insulin secretion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

SYT8 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYT8	NM_001394072.1	c.312G>C	p.Trp104Cys	missense_variant	3/8	ENST00000341958.4	NP_001381001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYT8	ENST00000341958.4	c.312G>C	p.Trp104Cys	missense_variant	3/8	5	NM_001394072.1	ENSP00000343691.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457388 Hom.: 0 Cov.: 42 AF XY: 0.00000138 AC XY: 1 AN XY: 725122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.354G>C (p.W118C) alteration is located in exon 4 (coding exon 4) of the SYT8 gene. This alteration results from a G to C substitution at nucleotide position 354, causing the tryptophan (W) at amino acid position 118 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Benign	0.88
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.19
Sift	Uncertain	0.020	D;D
Sift4G	Benign	0.11	T;T
Polyphen		1.0	D;D
Vest4		0.45
MutPred		0.62		Gain of disorder (P = 0.012);.;
MVP		0.24
MPC		0.52
ClinPred		0.69	D
GERP RS		3.5
Varity_R		0.27
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-1857169;